Kappa Delta Young Investigator Focuses on Tendon Healing, Remodeling

Award recognizes efforts of Nelly Andarawis-Puri, PhD


Nelly Andarawis-Puri, PhD

The winner of the 2018 Kappa Delta Young Investigator award, Nelly Andarawis-Puri, PhD, discovered biomechanical engineering as an undergraduate student at Columbia University. She went on to obtain her doctorate in bioengineering from the University of Pennsylvania and then a postdoctoral fellowship in orthopaedics at the Icahn School of Medicine at Mount Sinai. There, she worked with her postdoc mentor and coauthor, Evan L. Flatow, MD, studying the biologic and structural changes associated with onset of subrupture tendon damage using the in vino tendon fatigue rat model.

“My work in tendon research spans both basic science and translational applications,” she explained. As a predoctoral trainee at the University of Pennsylvania, working with Louis J. Soslowsky, PhD, she focused on the biomechanics of joint and tendon function, in particular the tendons of the shoulder.

After establishing that even a small injury to the supraspinatus tendon led to altered mechanics in the other healthy rotator cuff tendons, Dr. Andarawis-Puri realized the importance of early interventions for the health of the joint and not just the injured tendon. “Data from human cadaveric shoulders showed that the mechanical environment of the intact infraspinatus tendon is altered in association with injury to the supraspinatus tendon,” she wrote. Thus, small tears, such as those managed without surgery, could still lead to devastating changes in the remaining joint.

Motivated by her predoctoral and postdoctoral training, Dr. Andarawis-Puri adopted a multidisciplinary approach to determine the structural and regulatory role of the tendon extracellular matrix in the pathogenesis of tendinopathy and impaired healing of ruptured tendons. Her research incorporates biomechanics, biology, imaging, and mathematical modeling to elucidate the mechanisms of damage accumulation that underlie the pathogenesis of tendinopathy as well as the mechanisms that underlie effective scarless tendon healing.

The impact of fatigue

Dr. Andarawis-Puri’s research into the onset and pathogenesis of tendinopathy showed that fatigue-damage injuries do not innately remodel or repair. “Fatigue-damaged tendons attempt to repair induced damage but their ability to remodel is diminished after a certain threshold of damage is surpassed,” she wrote.

As a result, tendon injuries are often chronic, resulting from cumulative microtraumas and degeneration that ultimately lead to tendon failure. Using mouse and rat model, Dr. Andarawis-Puri investigated the temporal in vivo effects of subrupture fatigue injury. In addition, she studied the impact of fatigue damage on tendon healing and evaluated the effectiveness of various therapeutic modalities in improving healing. Finally, she investigated the effect of exercise and immobilization after tendon repair.

Her studies led to the following conclusions:

  • Damage begins to accumulate even from just one bout of sub-rupture fatigue loading.
  • Induced subrupture damage does not remodel and predisposes the tendon to further injury.
  • An increase in the severity of the initial induced damage correlates with a diminished repair attempt by the tendon.
  • The timing of exercise initiation after a fatigue injury will determine whether the exercise leads to repair or further degeneration of fatigue-damaged tendons (Fig. 1).
  • Exercise-led remodeling of fatigue-damaged tendons is associated with decreased apoptosis and an increase in the population of myofibroblasts.
  • Exercise can have a protective effect, but data are needed to guide timing and duration.
  • Inhibiting cell death, particularly through exercise, is a promising therapeutic intervention.


Fig. 1 Damage area fraction (DAF) for exercise-led remodeling and degeneration. Initiation of exercise one day after fatigue loading led to an increase in DAF. Initiation of exercise 14 days after fatigue loading led to a decrease in DAF. Modified from Bell and Boniello et al.

Courtesy of Bell R, Boniello MRR, Gendron NRR, et al

Based on the data she developed, Dr. Andarawis-Puri identified several mechanisms by which exercise could lead to remodeling, thereby opening avenues for diagnostics to help guide the timing of therapeutic exercises. According to Dr. Andarawis-Puri, “Physiologic loading, such as exercise, is a powerful modulator of the biological response of tissues.” The results of her studies showed that delayed initiation of exercise after onset of fatigue injury leads to structural remodeling. She has also shown that exercise reduces apoptosis and aggrecan production in fatigue-damaged tendons.

Scarless healing

Because ruptured tendons do not effectively heal due to the substitution of scar tissue for healthy tendon tissue, Dr. Andarawis-Puri investigated regenerative models that resulted in scarless tendon healing. Using adult Murphy Roths Large (MRL/MpJ) mice, which exhibit a regenerative capacity, she is investigating mechanisms that underlie adult regenerative healing.

“Shared characteristics between tissues that regenerate in MRL/MpJ mice suggest that the improved healing ability of these mice is either systemic or due to biological mechanisms that are common between tissues,” she wrote. “In contrast, the limitation of MRL/MpJ mice to regenerate all tissues supports that their regenerative ability is driven by the specific characteristics of the healing tissue.

“Although effective healing in MRL/MpJ is likely the result of cooperative roles between the systemic environment and the environment of the local tissue, we expect that the local tissue environment is integral to driving regeneration,” she continued. A series of studies generated the following lessons:

  • Scarless tendon healing is associated with early increased cell activity.
  • Scarless tendon healing is associated with a unique provisional ECM and growth factor environment.
  • The biologic response healing response of regenerative tendons does not correlate with systemic levels of key inflammatory cytokines.

“Contrary to the prevailing hypotheses of systemically driven tissue regeneration in MRL/MpJ, our data provide strong evidence to support further investigation of the role of the local tissue environment in driving regenerative healing,” she concluded.

Dr. Andarawis-Puri to present later in the week

Dr. Andarawis-Puri will receive the award during today’s Your Academy 2018 event and will present her award-winning paper, “Promoting Effective Tendon Healing and Remodeling” during the 2018 Annual Meeting of the Orthopaedic Research Society, on Sunday at the Hyatt Regency New Orleans.


Bell R, Boniello MRR, Gendron NRR, et al. 2015. Delayed exercise promotes remodeling in sub-rupture fatigue damaged tendons.33(6):919–925 Available from: www.ncbi.nlm.nih.gov/pubmed/25732052.